Viral infections remain among the most formidable causes of human and non-human animal morbidity and mortality worldwide. Effective preventions or therapies against most viral pathogens remain elusive. One of the most contemporary and catastrophic examples is the still rapidly expanding and pervasive worldwide pandemic of HIV (human immunodeficiency virus) infection and AIDS (acquired immune deficiency syndrome). Despite more than two decades of research to find effective preventative or therapeutic vaccines or drugs, surprisingly little progress has been made. The need for new effective preventative and therapeutic agents for HIV/AIDS and other potentially lethal viral diseases remains an urgent global priority.
Most efforts thus far to discover and develop new antiviral prophylactic or therapeutic drugs have focused on classical, non-peptidic “small molecules.” For example, nucleoside derivatives, such as AZT, which inhibit the retroviral reverse transcriptase, were among the first clinically active agents available commercially for anti-HIV therapy. Although very useful in some patients, the utility of AZT and other available anti-HIV drugs is limited by toxicity and insufficient therapeutic indices for fully adequate therapy. Also, given the dynamics of HIV infection (Coffin, Science 267: 483-489 (1995); and Cohen, Science 267: 179 (1995)), it has become increasingly apparent that agents acting as early as possible in the viral replicative cycle are needed to inhibit infection of newly produced, uninfected immune cells generated in the body in response to the virus-induced killing of infected cells. Also, it is essential to neutralize or inhibit new infectious virus produced by infected cells. Preferably, new agents, which act directly on the virus and/or upon the early viral host-cell interactions, to prevent virus/cell attachment and/or fusion and entry of virus into the cell are needed.
Peptidic or proteinaceous agents have historically been shunned in most drug discovery and development programs, typically based upon biased considerations of physicochemical properties, in vivo absorption and disposition, immunogenicity, and the like. However, in recent years, such biases have begun to sway, due to the increasing realization that the perceived problems can be circumvented, and that peptidic molecules offer tremendous structural diversity that may be exploited for development of novel therapeutics and preventions of many different kinds of diseases. Indeed, the foundation of the biotechnology industry is built substantially upon the potential of peptide- and protein-based therapeutics.
For example, in the field of HIV therapeutics a novel “rationally” constructed peptide molecule known as T-20 (Kilby, Nat. Med. 4: 1302-1307 (1998)) has been recently shown to be a potent inhibitor of HIV/cell fusion. Early clinical trials of T-20 are revealing considerable promise for inhibiting HIV infection in vivo (Cammack, Curr. Opin. Infect. Dis. 14: 13-16 (2001)). Thus, a distinct legitimacy is emerging in the HIV field for further exploration of peptide- and protein-based prevention and therapeutics of HIV infection and disease. Further reinforcing this momentum is the increasing realization that naturally occurring, non-mammalian peptides and proteins may offer entirely unanticipated new avenues for antiviral discovery and development. An outstanding example is the remarkable HIV-inactivating protein cyanovirin-N (Boyd et al., Antimicrob. Agents Chemother. 41: 1521-1530 (1997)). This agent is currently the subject of several major antiviral development programs in the United States under federal auspices, as well as elsewhere within the commercial sector. Clearly, there is great untapped potential for discovery and development of novel, non-mammalian antiviral peptides and proteins for unprecedented uses in prevention and therapeutics of viral diseases.
Accordingly, it is an object of the present invention to provide new antiviral peptides and proteins, as well as fusion proteins and conjugates thereof, and compositions comprising same, and methods of using same to inhibit viral infections. It is also an object of the present invention to provide nucleic acids, vectors, host cells, and related compositions and methods of use thereof to inhibit viral infections. It is yet another object of the present invention to provide antibodies. These and other objects and advantages of the present invention, as well as additional inventive features, will become apparent from the description provided herein.